AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes

Lauriane Cabon (1, 2) , Audrey Bertaux (1, 2) , Marie-Noelle Brunelle-Navas (1, 2) , Ivan Nemazanyy (3, 4) , Laurianne Scourzic (5, 6) , Laure Delavallée (1, 2) , Laura Vela (1, 2) , Mathieu Baritaud (1, 2) , Sandrine Bouchet (1, 2) , Cécile Lopez (5, 6) , Vu Quang Van (7) , Kevin Garbin (2, 1) , Danielle Chateau (2, 1) , Françoise Gilard (8, 9) , Marika Sarfati (7) , Thomas Mercher (5, 6) , Olivier Bernard (5, 6) , Santos A. Susin (1, 2)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 SU - Sorbonne Université
3 UPD5 - Université Paris Descartes - Paris 5
4 USPC - Université Sorbonne Paris Cité
5 U1170 Inserm - Hématopoïèse normale et pathologique
6 IGR - Institut Gustave Roussy
7 CHUM - Centre Hospitalier de l'Université de Montréal
8 IPS2 (UMR_9213 / UMR_1403) - Institut des Sciences des Plantes de Paris-Saclay
9 INRA - Institut National de la Recherche Agronomique

Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF-/Y ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF-/Y thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid β-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid β-oxidation (e.g., palmitic acid assimilation), the AIF-/Y thymocytes retrieved the ATP levels of the AIF +/Y cells. As a consequence, it was possible to significantly reestablish AIF-/Y thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.

Domaines: Sciences du Vivant [q-bio]

Lauriane Cabon, Audrey Bertaux, Marie-Noelle Brunelle-Navas, Ivan Nemazanyy, Laurianne Scourzic, et al.. AIF loss deregulates hematopoiesis and reveals different adaptive metabolic responses in bone marrow cells and thymocytes. Cell Death and Differentiation, 2018, 25, pp.983-1001. ⟨10.1038/s41418-017-0035-x⟩. ⟨hal-02365848⟩